1. Field of the Invention
The present invention relates to a method for the treatment of paralysis of the extremities induced by cerebral infarction. More specifically, it relates to a method comprising administering melatonin for the treatment of such paralysis of the extremities.
2. Discussion of the Background
Cerebral infarction is a severe cerebral dysfunction induced by cerebral ischemia or hypoxemia. With the increase of the aged population, the incidence of diseases or conditions, which may cause cerebral ischemia such as cerebral thrombosis and cerebral embolism, is increasing. Indeed, the number of patients suffering from cerebral infarction and having cerebral dysfunctions is continuously increasing.
One of the cerebral dysfunctions caused by cerebral infarction is paralysis of the extremities. When the hands and legs cannot perform their functions, the quality of life of such affected patients is significantly lowered and many burdens are placed on them and their families. For such patients, complete daily care is necessary.
For the treatment of severe cerebral infarction resulting in paralysis of the extremities, the use of a neuroprotective (e.g., as a glutamic acid antagonist, a channel antagonist, a radical scavenger, a neurogrowth factor, and a GABA agonist) has been proposed, but it requires further basic study. A central muscle relaxant, an agent for improving the microcirculation (e.g., an anti-platelet drug and an agent for accelerating deformation of erythrocytes), an agent for improving cerebral metabolism (e.g., an agent for enhancing the GABA system or the dopamine system and an agent for regulating the acetylcholine system), and the like have been complementarily administered in order to reduce adverse influences of cerebral infarction. Further, physiotherapies, such as a motorpathy, have been conducted in order to treat motor dysfunctions of the extremities caused by cerebral infarction.
Melatonin (N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide) is secreted from the pineal gland, and acts upon the suprachiasmatic nucleus to influence the formation of a diurnal rhythm (e.g., Chem. & Eng. News, vol. 45, p. 40 (1967)).
Since melatonin is characterized by the above physiological action, it is used for the treatment of disorders of the diurnal rhythm, such as sleep disorders, emotional disorders, immune hypofunctions, caused by, for example, time-difference (jetlag) (e.g., Barchas et al., Nature, vol. 214, p. 919 (1967) and A. Miles, D. Philbrick, CRC Crit. Rev. Clin. Lab. Sci., vol. 25, pp. 231-253 (1987)).
It was also reported that melatonin has antioxidative activity and functions as a free radical scavenger in vivo (Life Sci., vol. 60(25), pp. 2255-2271 (1997)).
The possibility that administered melatonin inhibits brain nitric oxide (NO) production after transient cerebral ischemia/reperfusion and reduces brain damage caused by free radicals has been mentioned (Guerrero J M. et al., J. Pineal Res., 23(1), 24-3 1(1997)).
Further, Sunghee Cho et al. (Brain Res., vol. 755(2), pp.335-338 (1997)) described that intraperitoneally administered melatonin, especially prior to cerebral ischemia or during reperfusion, protects CAl hippocampal neurons against ischemic injury. However, it has been known that severe cerebral dysfunctions, which may result in paralysis of the extremities, do not occur in cases where the injury caused by cerebral ischemia is restricted to the hippocampus. Also, no extra-hippocampal damage was observed (Ginsburg et al., Rodent models of Cerebral Ischemia, Stroke, vol. 20, pp. 1627-1642 (1989)).
In addition, it has been reported that in models of cerebral ischemia induced by ligating the middle cerebral artery, the brain necroses (by observation of tissues under a microscope) of rats having no detectable level of blood melatonin after pinealectomy are significantly greater than in normal rats (Manev H. et al., FASEB J, vol. 10(13), pp. 1546-1551 (1996)). However, this report does not suggest the role of exogenous melatonin in the presence of endogenous melatonin, since cerebral ischemia was not induced in the presence of endogenous melatonin.
It has been reported that blood (endogenous) melatonin in old men of the age of 82 to 86 is about one quarter of that in young men of the age of 21 to 25 (about 80 pg/ml) (Reiter R. J., Acta Neurobiol. Exp., vol. 54, pp. 31-39 (1994) and Reiter R. J., FASEB J., vol. 9, pp. 526-533 (1995)).
On the other hand, it is described in J. Clin. Endocrinol. Metab., vol. 61, pp. 1214-1216 (1985); Life Sci., vol. 37, pp. 489-495 (1985); Br. J. Clin. Pharmacol., vol. 19, pp. 517-521 (1985); and Neuroendocrinology, vol. 39, pp. 307-313 (1984) that orally administered melatonin circulates in the blood and passes through the blood-brain barrier. Also, intravenously administered melatonin was shown to pass into the brain (Pineal Res., vol. 5, pp. 437-453 (1988) and Int. J. Rds. Appl. Instrum. [B], vol. 18, pp. 357-362 (1991)).
WO 97/20555 (corresponding to U.S. Pat. No. 5,700,828) discloses that the mild motor dysfunction of a foot-fault rate of 0.01 in rats caused by cerebral ischemia can be lowered to a foot-fault rate of 0.002 by administration of a "rescue" solution containing melatonin, kynurenine and others to the cerebral ischemic rat. The foot fault rate of the non-treated control rats was 0.005 in the experiment.
However, in the transient ischemic rat model employed in WO 97/20555, wherein the bilateral vertebral arteries were ligated (in practice, burned off) and one day later the bilateral internal carotid arteriae were occluded for 10 minutes (Stroke, vol. 10, pp. 267-272 (1979)), the rats would suffer from neuropathies (e.g., extremital peripheral nerve disturbances, muscle disturbances, equilibrium disturbances, and visual disturbances) resulting from causes other than cerebral infarction. Ataxia would be caused by the neuropathies, leading to the lowering in foot-fault rate. In fact, no cerebral infarction could be demonstrated with other experiments in transient ischemic rats produced by the procedures as above. Further, the motor dysfunction of a foot-fault rate of 0.01 in the transient ischemic rats of WO 97/20555 is not so severe as to cause paralysis of extremities.
The foot fault rate is a known term, and is generally determined according to the Hernandez-Schallert foot-fault test, wherein rats are forced to walk on a bar 3 to 6 cm in diameter, and the percentage of missed steps (slipped down) is calculated. The rate is the proportion of the missed steps after ischemia to the missed steps before ischemia.
Accordingly, WO 97/20555 fails to suggest the treatment of severe cerebral infarction which may causes paralysis of the extremities, or severe paralysis of the extremities resulting from cerebral infarction.
Thus, there remains a need for an effective method capable of treating paralysis of the extremities caused by cerebral infarction.